Haidi Yang

Activation of miR-34a/SIRT1/p53 signaling contributes to cochlear hair cell apoptosis: implications for age-related hearing loss

The molecular mechanisms underlying age-related hearing loss are not fully understood, and currently, there is no treatment for this disorder. MicroRNAs have recently been reported to be increasingly associated with age-related diseases and are emerging as promising therapeutic targets. In this study, miR-34a/Sirtuin 1 (SIRT1)/p53 signaling was examined in cochlear hair cells during aging. MiR-34a, p53 acetylation, and apoptosis increased in the cochlea of C57BL/6 mice with aging, whereas an age-related decrease in SIRT1 was observed. In the inner ear HEI-OC1 cell line, miR-34a overexpression inhibited SIRT1, leading to an increase in p53 acetylation and apoptosis. Moreover, miR-34a knockdown increased SIRT1 expression and diminished p53 acetylation, and apoptosis. Additionally, resveratrol, an activator of SIRT1, significantly rescued miR-34a overexpression-induced HEI-OC1 cell death and significantly reduced hearing threshold shifts and hair cell loss in C57BL/6 mice after a 2-month administration. Our results support a link between age-related cochlear hair cell apoptosis and miR-34a/SIRT1/p53 signaling, which may serve as a potential target for age-related hearing loss treatment.

SIRT1 expression in the cochlea and auditory cortex of a mouse model of age-related hearing loss.

SIRT1 is a highly conserved NAD(+)-dependent protein deacetylase known to have protective effects against a variety of age-related diseases. However, there is a lack of information concerning SIRT1 expression in the cochlea and auditory cortex of C57BL/6 mice, a mouse model of age-related hearing loss. Using RT-PCR and immunohistochemistry, we show that SIRT1 is abundantly expressed in the inner hair cells, strial marginal cells, strial intermediate cells, type I and type IV fibrocytes of the spiral ligament and spiral ganglion neurons. In addition, moderate SIRT1 is also detected in the outer hair cells and neurons of the auditory cortex. Associated with elevated hearing thresholds and hair cells loss during aging, there is also a significant reduction of SIRT1 expression in the cochlea and auditory cortex. The expression pattern of SIRT1 in the peripheral and central auditory system suggests that SIRT1 may play an important role in auditory function and therefore may serve as a protective molecule against age-related hearing loss.

Circulating miR-34a levels correlate with age-related hearing loss in mice and humans.

Age-related hearing loss (AHL) is a progressive neurodegenerative disease that is largely silent in its initial stages. There is no sensitive blood biomarker for diagnosis or early detection of AHL. MicroRNAs (miRNAs or miRs) are abundant and highly stable in blood, and have been recently described as powerful circulating biomarkers in a wide range of diseases. In the present study, we identified concordant increases in miR-34a levels in the cochlea, auditory cortex, and plasma of C57BL/6 mice during aging. These increases were accompanied by elevated hearing thresholds and greater loss of hair cells. Levels of miR-34a targets, silent information regulator 1 (SIRT1), B-cell lymphoma-2 (Bcl-2), and E2F transcription factor 3 (E2F3), in the cochlea, auditory cortex, and plasma decreased with aging inversely to miR-34a. Moreover, plasma miR-34a levels were significantly higher in patients with AHL compared with controls who had normal hearing and had a receiver-operating characteristic curve that distinguished AHL patients from controls. However, SIRT1, Bcl-2, and E2F3 showed no correlation with AHL in humans. In summary, circulating miR-34a level may potentially serve as a useful biomarker for early detection of AHL.

The Diagnostic Value of Narrow-Band Imaging for the Detection of Nasopharyngeal Carcinoma

Objectives: To evaluate the diagnostic value of narrow-band imaging (NBI) for the detection of nasopharyngeal carcinoma (NPC). Study Design: Prospective study. Setting: Tertiary medical center. Subjects and Methods: Between December 2009 and June 2010, a total of 1,854 patients were examined by means of an electronic nasopharyngolaryngoscope equipped with conventional white light (WL) and an NBI system. The sensitivity, specificity and positive/negative predictive values for detecting NPC were calculated and compared. Results: Of these patients, 62 cases (3.34%) were pathologically confirmed as NPC. The sensitivity, specificity, positive predictive value and negative predictive value for detecting NPC significantly increased from 90.3, 75.4, 11.3 and 99.6% with WL up to 100, 99.2, 81.6 and 100% with NBI, respectively. Conclusion: Our findings suggested that NBI endoscopy might serve as an ideal tool in the detection of NPC.

Evaluation of auditory cortical development in the early stages of post cochlear implantation using mismatch negativity measurement

Objective The aim of this study was to investigate auditory cortical development using mismatch negativity (MMN) in prelingual severe-to-profound hearing-impaired children from the stage of cochlear implant (CI) power-up to 6 months after power-up. Method Eighteen children were recruited and examined at the stage of CI initial power-up (M0), as well as several follow-up periods, that is, 1 month (M1), 3 months (M3), and 6 months (M6) after CI power-up. The MMN responses were measured using a 128-Channel Dense Array EEG System. The group average and individual MMN analysis were used to investigate the longitudinal changes of the MMN characteristics. The relationship between MMN characteristics and scores of categories of auditory performance (CAP) was also investigated. Results Although the MMN incidence was much lower at the periods of M0 and M1, significantly higher MMN incidence was found in M3 and M6. The MMN latencies decreased significantly from M3 to M6, but no significant difference in the amplitudes was found between these periods. There was a negative correlation between the increment of CAP scores and decrement of MMN latency from M3 to M6. Conclusion MMN incidence increment and latency decrement are likely to be the objective and noninvasive indicators for evaluating auditory central development at an early stage in children after cochlear implantation. Moreover, the latency decrement from M3 to M6 correlated significantly with the increment of the CAP scores, indicating a fast maturation period, which might be a key period for auditory rehabilitation.

The characteristic and changes of the event-related potentials (ERP) and brain topographic maps before and after treatment with rTMS in subjective tinnitus patients.

Objectives To compare the event-related potentials (ERPs) and brain topographic maps characteristic and change in normal controls and subjective tinnitus patients before and after repetitive transcranial magnetic stimulation (rTMS) treatment. Methods and Participants The ERPs and brain topographic maps elicited by target stimulus were compared before and after 1-week treatment with rTMS in 20 subjective tinnitus patients and 16 healthy controls. Results Before rTMS, target stimulus elicited a larger N1 component than the standard stimuli (repeating sounds)in control group but not in tinnitus patients. Instead, the tinnitus group pre-treatment exhibited larger amplitude of N1 in response to standard stimuli than to deviant stimuli. Furthermore tinnitus patients had smaller mismatch negativity (MMN) and late discriminative negativity (LDN)component at Fz compared with the control group. After rTMS treatment, tinnitus patients showed increased N1 response to deviant stimuli and larger MMN and LDN compared with pre-treatment. The topographic maps for the tinnitus group before rTMS -treatment demonstrated global asymmetry between the left and right cerebral hemispheres with more negative activities in left side and more positive activities in right side. In contrast, the brain topographic maps for patients after rTMS-treatment and controls seem roughly symmetrical. The ERP amplitudes and brain topographic maps in post-treatment patient group showed no significant difference with those in controls. Conclusions The characterical changes in ERP and brain topographic maps in tinnitus patients maybe related with the electrophysiological mechanism of tinnitus induction and development. It can be used as an objective biomarker for the evaluation of auditory central in subjective tinnitus patients. These findings support the notion that rTMS treatment in tinnitus patients may exert a beneficial effect.

Toward an Understanding of Auditory Evoked Cortical Event-Related Potentials: Characteristics and Classification

Abstract Objective: To investigate the characteristics of auditory evoked cortical ERP components P1-N1-P2 and MMN and explore a practical way for ERP waveform identification and classification. Methods: Thirty right-handed normally hearing volunteers participated in the present study, age ranging from 20 to 40 years old, 14 males and 16 females. All the volunteers reported no history of auditory, neurological or mental disorder. The event related potential (ERP) components (i.e. P1-N1-P2 complex and mismatch negativity (MMN)) were measured using the 128-electrode channels EGI system. Results: Three different categories of ERP responses were classified on the basis of waveform configuration, size of the peak amplitude and the number of peaks together with scalp distribution of MMN. Ten participants (33.3%) had well defined ERP responses, 13 (43.3%) showed moderately defined ERP responses, and seven (23.3%) had poorly defined ERP responses. Although there were no significant differences in P1, P2, and MMN latencies, participants with the poorly defined ERP waves had significantly longer N1 latency than that in subjects with well defined ERP waves. In addition, significantly lower MMN amplitudes were also found in this group. Conclusion: Combining a waveform classification method and the MMN scalp distribution pattern, together with quantitative ERP response analysis, may provide more reliable and practical means for clinical application.

Effect of the combination of balloon Eustachian tuboplasty and tympanic paracentesis on intractable chronic otitis media with effusion

OBJECTIVE To evaluate the effect of the combination of balloon Eustachian tuboplasty (BET) and tympanic paracentesis (TP) on intractable chronic otitis media with effusion (COME). METHODS Ninety patients with intractable COME were included and randomly assigned to three groups: BET only (30 patients), BET+paracentesis (30 patients), and paracentesis only (30 patients). Otic endoscopic findings and tympanograms were recorded before the surgery and at the month 1, month 3, and month 6 follow-up evaluations. RESULTS Both the BET only and BET+paracentesis groups achieved better outcomes than the paracentesis group. The BET+paracentesis group exhibited better otic endoscopic scores than the BET only group (p<0.05) at 1month post-operation. However, no significant difference was found at month 3 or month 6 post-operation. No significant difference in the tympanograms was observed between these two groups at month 1, month 3, or month 6 post-operation. The otic endoscopic sign scores improved from month 1 to month 6 in the BET only group and from month 1 to month 3 in the BET+paracentesis group. The conversion of type B tympanograms improved from month 1 to month 6 in the BET and BET+paracentesis groups but not in the paracentesis only group. CONCLUSIONS Our results suggested that the combination of BET and TP was effective for intractable COME and can help shorten the recovery period for middle ear effusion.

miR-34a/Bcl-2 signaling pathway contributes to age-related hearing loss by modulating hair cell apoptosis

MicroRNAs, such as miR-34, have been reported to influence age-related diseases. In this study, we explored the role of the miR-34a/Bcl-2 signaling pathway in age-related hearing loss (AHL). Using an AHL mouse model (C57BL/6), we found that the expression of miR-34a in the cochlea increased with age, whereas expression of Bcl-2 decreased. Increasing the amount of a miR-34a mimetic in a mouse auditory cell line (HEI-OC1) inhibited Bcl-2, leading to enhanced apoptosis; in contrast, miR-34a inhibition produced the opposite effect. Our results support a link between age-related cochlear hair cell apoptosis and miR-34a/Bcl-2 signaling. The latter may thus serve as a potential target for AHL therapy.

Activation of miR-34a impairs autophagic flux and promotes cochlear cell death via repressing ATG9A: implications for age-related hearing loss

Age-related hearing loss is a major unresolved public health problem. We have previously elucidated that the activation of cochlear miR-34a is correlated with age-related hearing loss in C57BL/6 mice. A growing body of evidence points that aberrant autophagy promotes cell death during the development of multiple age-related diseases. The aim of this study was to investigate the role of miR-34a-involved disorder of autophagy in the pathogenesis of age-related hearing loss. Our results showed that miR-34a expression was markedly upregulated in the aging cochlea accompanied with impairment of autophagic flux. In the inner ear HEI-OC1 cell line, miR-34a overexpression resulted in an accumulation of phagophores and impaired autophagosome–lysosome fusion, and led to cell death subsequently. Notably, autophagy-related protein 9A (ATG9A), an autophagy protein, was significantly decreased after miR-34a overexpression. Knockdown of ATG9A inhibited autophagy flux, which is similar to the effects of miR-34a overexpression. Moreover, ursodeoxycholic acid significantly rescued miR-34a-induced HEI-OC1 cell death by restoring autophagy activity. Collectively, these findings increase our understanding of the biological effects of miR-34a in the development of age-related hearing loss and highlight miR-34a as a promising therapeutic target for its treatment.